WO2019094934A1 - Process for preparing tapinarof - Google Patents
Process for preparing tapinarof Download PDFInfo
- Publication number
- WO2019094934A1 WO2019094934A1 PCT/US2018/060749 US2018060749W WO2019094934A1 WO 2019094934 A1 WO2019094934 A1 WO 2019094934A1 US 2018060749 W US2018060749 W US 2018060749W WO 2019094934 A1 WO2019094934 A1 WO 2019094934A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- salt
- viii
- iii
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 22
- ZISJNXNHJRQYJO-CMDGGOBGSA-N 5-[(e)-2-phenylethenyl]-2-propan-2-ylbenzene-1,3-diol Chemical compound C1=C(O)C(C(C)C)=C(O)C=C1\C=C\C1=CC=CC=C1 ZISJNXNHJRQYJO-CMDGGOBGSA-N 0.000 title abstract description 8
- 229940070118 tapinarof Drugs 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 681
- 238000000034 method Methods 0.000 claims abstract description 204
- 230000008569 process Effects 0.000 claims abstract description 174
- 239000012453 solvate Substances 0.000 claims abstract description 119
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 882
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 186
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 160
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 158
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 101
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 75
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 75
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 60
- 229940117916 cinnamic aldehyde Drugs 0.000 claims description 57
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 54
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 50
- 230000002140 halogenating effect Effects 0.000 claims description 48
- 230000000911 decarboxylating effect Effects 0.000 claims description 43
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical group CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 41
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 40
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 230000003301 hydrolyzing effect Effects 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 29
- 239000003795 chemical substances by application Substances 0.000 claims description 28
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 27
- 238000010438 heat treatment Methods 0.000 claims description 27
- 239000000654 additive Substances 0.000 claims description 24
- 230000000996 additive effect Effects 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims description 20
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 20
- 238000007363 ring formation reaction Methods 0.000 claims description 20
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 18
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
- 238000009833 condensation Methods 0.000 claims description 17
- 230000005494 condensation Effects 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 15
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 14
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical group [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- CLPHAYNBNTVRDI-UHFFFAOYSA-N ditert-butyl propanedioate Chemical group CC(C)(C)OC(=O)CC(=O)OC(C)(C)C CLPHAYNBNTVRDI-UHFFFAOYSA-N 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 4
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 229950009390 symclosene Drugs 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000013078 crystal Substances 0.000 abstract description 18
- 239000000543 intermediate Substances 0.000 abstract description 5
- OWLUNSCGLTYXIW-CMDGGOBGSA-N 2-chloro-5-[(E)-2-phenylethenyl]-2-propan-2-ylcyclohexane-1,3-dione Chemical compound ClC1(C(CC(CC1=O)\C=C\C1=CC=CC=C1)=O)C(C)C OWLUNSCGLTYXIW-CMDGGOBGSA-N 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 60
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 26
- 239000000203 mixture Substances 0.000 description 21
- -1 2-substituted resorcinols Chemical class 0.000 description 17
- NXRGKFVQYZGDIY-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1.CC1=CC=CC(C)=N1 NXRGKFVQYZGDIY-UHFFFAOYSA-N 0.000 description 13
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 150000002576 ketones Chemical class 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 125000002883 imidazolyl group Chemical group 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OMVZUSOTKKSRIM-CMDGGOBGSA-N 2-[(E)-7-methyl-5-oxo-1-phenyloct-1-en-3-yl]propanedioic acid Chemical compound CC(CC(CC(/C=C/C1=CC=CC=C1)C(C(=O)O)C(=O)O)=O)C OMVZUSOTKKSRIM-CMDGGOBGSA-N 0.000 description 6
- HBUVXYWESGKFMI-JMQWPVDRSA-N (5e,7e)-2-methyl-8-phenylocta-5,7-dien-4-one Chemical compound CC(C)CC(=O)\C=C\C=C\C1=CC=CC=C1 HBUVXYWESGKFMI-JMQWPVDRSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000003880 polar aprotic solvent Substances 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- ZKVYMYVNXAYKRB-OUKQBFOZSA-N diethyl 2-[(E)-7-methyl-5-oxo-1-phenyloct-1-en-3-yl]propanedioate Chemical compound CC(CC(CC(/C=C/C1=CC=CC=C1)C(C(=O)OCC)C(=O)OCC)=O)C ZKVYMYVNXAYKRB-OUKQBFOZSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004896 high resolution mass spectrometry Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 3
- DFQSZPBOUCYWPQ-CMDGGOBGSA-N 7-methyl-5-oxo-3-[(E)-2-phenylethenyl]octanoic acid Chemical compound CC(CC(CC(CC(=O)O)\C=C\C1=CC=CC=C1)=O)C DFQSZPBOUCYWPQ-CMDGGOBGSA-N 0.000 description 3
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 239000012455 biphasic mixture Substances 0.000 description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229940127557 pharmaceutical product Drugs 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- YGOPULMDEZVJGI-UHFFFAOYSA-N 1-(2-chlorophenyl)ethane-1,2-diol Chemical group OCC(O)C1=CC=CC=C1Cl YGOPULMDEZVJGI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)CC(CC(C(C(*)=O)C(O)=O)C=Cc1ccccc1)=O Chemical compound CC(C)CC(CC(C(C(*)=O)C(O)=O)C=Cc1ccccc1)=O 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 2
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical class O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 2
- ZKBBUZRGPULIRN-UHFFFAOYSA-N diethyl 2,2-diethylpropanedioate Chemical compound CCOC(=O)C(CC)(CC)C(=O)OCC ZKBBUZRGPULIRN-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- FCALIWQDLNLSFF-MDZDMXLPSA-N methyl 7-methyl-5-oxo-3-[(E)-2-phenylethenyl]octanoate Chemical compound CC(CC(CC(CC(=O)OC)\C=C\C1=CC=CC=C1)=O)C FCALIWQDLNLSFF-MDZDMXLPSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- ABKRGXBSJGYCFA-UHFFFAOYSA-N 1-(2-phenylethenyl)-2-propan-2-ylbenzene Chemical compound CC(C)C1=CC=CC=C1C=CC1=CC=CC=C1 ABKRGXBSJGYCFA-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- IHQCAYWICDJUCP-VOTSOKGWSA-N O=C(CC(CC1=O)/C=C/c2ccccc2)C1Cl Chemical compound O=C(CC(CC1=O)/C=C/c2ccccc2)C1Cl IHQCAYWICDJUCP-VOTSOKGWSA-N 0.000 description 1
- 206010074268 Reproductive toxicity Diseases 0.000 description 1
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- 229920006362 Teflon® Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
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- 238000013019 agitation Methods 0.000 description 1
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- RCTOVWPTGOZSPJ-UHFFFAOYSA-N benzyl(ethyl)azanium;chloride Chemical compound Cl.CCNCC1=CC=CC=C1 RCTOVWPTGOZSPJ-UHFFFAOYSA-N 0.000 description 1
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- 125000004432 carbon atom Chemical group C* 0.000 description 1
- OSVXSBDYLRYLIG-UHFFFAOYSA-N chlorine dioxide Inorganic materials O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 1
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- 235000005911 diet Nutrition 0.000 description 1
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- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
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- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
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- 230000007696 reproductive toxicity Effects 0.000 description 1
- 231100000372 reproductive toxicity Toxicity 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- ARCJQKUWGAZPFX-UHFFFAOYSA-N stilbene oxide Chemical class O1C(C=2C=CC=CC=2)C1C1=CC=CC=C1 ARCJQKUWGAZPFX-UHFFFAOYSA-N 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
- C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
- C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
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- C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
- C07C37/07—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation with simultaneous reduction of C=O group in that ring
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- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/213—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings
- C07C49/217—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the aromatic rings
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
- C07C49/683—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings having unsaturation outside the aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
- C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/24—Quinones containing halogen
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/347—Saturated compounds containing more than one carboxyl group containing keto groups
- C07C59/353—Saturated compounds containing more than one carboxyl group containing keto groups containing rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- Some embodiments of the present invention provides a processes for the preparation of the compound of Formula (I) or a salt thereof and to novel intermediates used therein
- Some embodiments of the present invention describe a pharmaceutical composition which comprises a compound of Formula (I) or a salt or solvate thereof prepared according to the processes of the present invention and a pharmaceutically acceptable excipient.
- Figure 1 shows an X-ray powder diffraction (XRPD) pattern of the compound of Formula (I) in crystalline solid state form (Form 1).
- Figure 2 shows an X-ray powder diffraction (XRPD) pattern of an acetic acid solvate of the compound of Formula (I) in crystalline solid state form.
- XRPD X-ray powder diffraction
- Schamp et al. discloses a synthesis of simple 2-substituted resorcinols such as 2-methyl-, 2-benzyl- and 2-acetylresourcinol from the corresponding 1,3-cyclohexanediones.
- the reported conditions involve the chlorination of the 1,3-cyclohexanediones followed by elimination of HC1 upon heating with a 25% solution of dry hydrogen chloride in dimethylformamide.
- Some embodiments describe processes for making compounds of Formula (I) or a salt or solvate thereof comprising at least one of process steps (a) to (c).
- the processes of the present invention may include one, two or all three of process steps (a), (b) and (c).
- the compound of Formula (I) prepared by process (a), (b) or (c) is in crystalline solid state form.
- the compound of Formula (I) in crystalline solid state form (Form 1) which has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- the compound of Formula (I) in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- X is CI
- the reaction is carried out using a chlorination reagent selected from the group consisting of l,3-dichloro-5,5- dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS) and trichloroisocyanuric acid (TCCA).
- a chlorination reagent selected from the group consisting of l,3-dichloro-5,5- dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS) and trichloroisocyanuric acid (TCCA).
- the chlorination reagent is DCDMH.
- the conversion of the compound of Formula (II) or a salt thereof to a compound of Formula (I) or a salt thereof is carried out in a suitable solvent and optionally with an additive material.
- the conversion of the compound of Formula (II) or a salt thereof to give a compound of Formula (I) or a salt thereof is carried out in a suitable solvent which is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), dimethylacetamide (DMAC) and sulfolane.
- a suitable solvent which is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), dimethylacetamide (DMAC) and sulfolane.
- the conversion of the compound of Formula (II) or a salt thereof to a compound of Formula (I) or a salt thereof is carried out in the presence of an additive reagent which is a quaternary ammonium salt, for example a quaternary ammonium bromide salt or a quaternary ammonium chloride salt.
- an additive reagent which is a quaternary ammonium salt, for example a quaternary ammonium bromide salt or a quaternary ammonium chloride salt.
- the quaternary ammonium bromide salt is tetrabutylammonium bromide.
- the quaternary ammonium chloride salt is selected from the group consisting of benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethyl ammonium chloride and tetram ethyl ammonium chloride. In some embodiments the quaternary ammonium chloride salt is tetraethyl ammonium chloride.
- the conversion of the compound of Formula (II) or a salt thereof to give a compound of Formula (I) or a salt or a solvate thereof in the presence of an additive reagent is carried out in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutyl ketone. It was found that acetonitrile provided the best combination of solubility and high boiling point. In some embodiments this conversion is carried out in a solvent which is acetonitrile. [0031] Embodiments of the present disclosure describe a compound of Formula (Ila) or a salt thereof
- the compound of Formula (I) may be prepared in the form of an acetic acid solvate thereof.
- Some embodiments of the present disclosure describe a compound of Formula (I) in the form of an acetic acid solvate thereof. It has been found that formation of the acetic acid solvate of the compound of Formula (I) provides impurity and colour purging capabilities to the process of the invention. The acetic acid solvate of the compound of Formula (I) can thereafter be converted into the compound of Formula (I).
- an acetic acid solvate of the compound of Formula (I) in crystalline solid state form In some embodiments, there is provided, an acetic acid solvate of the compound of Formula (I) in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2. In another embodiment there is provided an acetic acid solvate of the compound of Formula (I) in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- an acetic acid solvate of the compound of Formula (I) in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the process further comprises a step of recrystallization of the compound of Formula (I) or a salt or solvate thereof.
- recrystallization is carried out using methanol and water.
- conversion of a compound of Formula (VI) or a salt thereof into a compound of Formula (III) or a salt thereof comprises a decarboxylation of the compound of Formula (VI) or a salt thereof to form the compound of Formula (V) or a salt thereof
- R is C 1-4 alkyl
- conversion of a compound of Formula (VI) or a salt thereof into a compound of Formula (V) or a salt thereof comprises decarboxylation in the presence of a base.
- the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine).
- the base is triethylamine.
- R is methyl, ethyl, propyl, or butyl. In some embodiments R is t-butyl. In some embodiments R is methyl.
- esterification of a compound of Formula (V) or a salt thereof to a compound of Formula (IV) or a salt thereof is performed using methanol, for example esterification is performed using methanol and hydrochloric acid.
- cyclization of a compound of Formula (IV) or a salt thereof to a compound of Formula (III) or a salt thereof is performed using potassium tert- butoxide.
- the compound of Formula (III) or a salt thereof is acidified and isolated by precipitation with methylcyclohexane.
- the conversion of a compound of Formula (VI) or a salt thereof into a compound of Formula (III) or a salt thereof is telescoped such that the compounds of Formula (V) or a salt thereof and Formula (IV) or a salt thereof are not isolated.
- the compound of Formula (III) or a salt thereof may be converted into a compound of Formula (I) or a salt or solvate thereof by methods described herein (e.g. process step (a)) or by methods known to the person skilled in the art (e.g. by methods described in Kronenwerth, M. et al).
- the compound of Formula (III) or a salt thereof may be converted into a compound of Formula (I) or a salt or solvate thereof by process step (a).
- conversion of a compound of Formula (IX) or a salt thereof into a compound of Formula (VI) or a salt thereof comprises the condensation of the compound of Formula (IX) or a salt thereof with methyl isobutyl ketone to form the compound of Formula (VIII) or a salt thereof
- Ri and R 2 are independently C 1-4 alkyl
- condensation of a compound of Formula (IX) or a salt thereof into a compound of Formula (VIII) or a salt thereof is performed using lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the conversion of a compound of Formula (VIII) or a salt thereof into a compound of Formula (VII) or a salt thereof comprises the addition of a malonic ester which is di-tert-butyl malonate or diethyl malonate.
- the conversion of a compound of Formula (IX) or a salt thereof into a compound of Formula (VI) or a salt thereof is telescoped such that the compounds of Formula (VII) and Formula (VIII) or salts thereof are not isolated.
- Li C MR (176 MHz, DMSO) ⁇ 208.1 (C), 167.7 (C), 167.6 (C), 136.6 (C), 131.4 (CH), 128.9 (CH), 127.4 (CH), 125.9 (CH), 61.0 (CH2), 60.8 (CH2), 55.0 (CH), 51.3 (CH2), 44.8 (CH2), 37.7 (CH), 23.8 (CH),22.3 (CH3), 22.2 (CH3), 13.9 (CH3), 13.9 (CH3).
- the compound of Formula (VI) or a salt thereof may be converted into a compound of Formula (I) or a salt or solvate thereof by methods described herein (e.g. process steps (a) and (b)) or by methods known to the person skilled in the art (e.g. by methods described in Kronenwerth, M. et al).
- the compound of Formula (VI) or a salt thereof may be converted into a compound of Formula (I) or a salt or solvate thereof by process steps (a) and (b).
- the process further comprises purifying the compound of Formula (I) or a salt or solvate thereof.
- the purifying comprises crystallization of the compound of Formula (I) or a salt or solvate thereof.
- the compound of Formula (I) is a crystal form described in any embodiment described herein.
- the compound of Formula (I) is crystal form 1.
- the compound of Formula (I) is an anhydrous crystal.
- the compound of Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0. ⁇ 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0. ⁇ 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0. ⁇ 2 ⁇ experimental error).
- X is CI.
- the aromatizing is carried out in a suitable solvent and optionally with an additive reagent.
- the aromatizing is carried out in a suitable solvent which is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), 1,3 -dimethyl - 3,4,5,6-tetrahydro-2(lH)-pyrimidinone.
- the aromatizing is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutyl ketone.
- the aromatizing is carried out in acetonitrile in the presence of an additive reagent.
- the additive reagent is a quaternary ammonium salt.
- the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride and tetramethylammonium chloride.
- the quaternary ammonium salt is tetraethylammonium chloride.
- the aromatizing is carried out in acetonitrile with tetraetylammonium chloride.
- the process further comprises halogenating a compound of Formula (III) or salt thereof
- the halogenating agent is selected from l,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA).
- DCDMH l,3-dichloro-5,5-dimethylhydantoin
- NCS N-chlorosuccinimide
- TCCA trichloroisocyanuric acid
- the halogenating agent is DCDMH and the compound of Formula (II) or a salt thereof is a compound of Formula (Ila) or a salt thereof:
- the halogenating is carried out in methanol.
- the halogenation agent is DCDMH and the halogenation is carried out in methanol.
- the process further comprises cyclizing a compound of Formula (IV) or salt thereof
- R is C 1-4 alkyl, to obtain the compound of Formula (III) or a salt thereof.
- R is selected from the group consisting of methyl, ethyl, propyl, or butyl.
- R is t-butyl.
- R is methyl.
- the cyclization comprises contacting the compound of Formula (IV) or a salt thereof, with a base.
- the cyclization is performed using potassium tert-butoxide.
- the cyclization is carried out in 2-methyltetrahydrofuran.
- the cyclization comprises treating a compound of Formula (IV) or a salt thereof, for example a compound of (IVa) or a salt thereof, with potassium tert-butoxide in 2- methyltetrahydrofuran.
- the compound of Formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.
- the process further comprises esterifying a compound of Formula (V) or salt thereof
- the esterifying is carried out using methanol and hydrochloric acid to obtain compound (IV).
- the esterifying comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the process further comprising decarboxylating a compound of Formula (VI) or a s
- the decarboxylating comprises the presence of a base.
- the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine).
- the base is trimethylamine.
- the decarboxylating comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- the process further comprises hydrolyzing a compound of Formula (VII) or a salt thereof
- each Ri and R 2 is independently C 1-4 alkyl; to obtain the compound of Formula (VI) or a salt thereof.
- each of Ri and R 2 is ethyl (Vila).
- the hydrolyzing comprises treating the compound of Formula (VII) or a salt thereof, with sodium hydroxide.
- the hydrolyzing comprises treating the compound of Formula (VII) or a salt thereof with sodium hydroxide in ethanol.
- the process comprises hydrolyzing a compound of Formula (Vila) or a salt thereof comprising treating the compound of Formula (Vila) or a salt thereof with sodium hydroxide in ethanol.
- the process further comprises adding a dialkyl malonic ester (RiO(0)C-CH 2 -C(0)OR 2 wherein each Ri and R 2 is independently C 1-4 alkyl), to a compound of Formula (VIII) or a salt thereof
- the dialkyl malonic ester is di-tert-butylmalonate or diethyl malonate.
- the adding comprises contacting the dialkyl malonic ester with the compound of Formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.
- the process further comprises condensing trans- cinnamaldehyde (compound of Formula (IX)) or a salt thereof
- the condensing comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- R is C alkyl; c) cyclizing the compound of Formula (IV) or a salt thereof to form a compound of Formula (III) or a salt thereof, d) halogenating the compound of Formula (III) or a salt thereof to form a compound of Formula (II) or a salt thereof,
- X is selected from Br, CI and I; and e) aromatizing the compound of Formula (II) or a salt thereof to form the compound of Formula (I) or a salt or solvate thereof.
- the process further comprises isolating the compound of Formula (III) or a salt thereof in step c). In some embodiments the process comprises isolating the compound of Formula (II) or a salt thereof in step d). In some embodiments the process further comprises purifying the compound of Formula (I) or a salt or solvate thereof obtained from step e). In some embodiments the purifying comprises crystallization of the compound of Formula (I) or a salt or solvate thereof. In some embodiments the compound of Formula (I) is a crystal form described in any embodiment described herein. In some embodiments the compound of Formula (I) is crystal form 1. In some embodiments the compound of Formula (I) is an anhydrous crystal.
- the compound of Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0. ⁇ 2 ⁇ experimental error).
- the decarboxylating of a compound of Formula (VI) or a salt thereof in step a) comprises the presence of a base.
- the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine).
- the base is trimethylamine.
- the decarboxylating comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- R of the compound of Formula (IV) or a salt thereof in step b) is selected from the group consisting of methyl, ethyl, propyl, or butyl. In some embodiments R of the compound of Formula (IV) or a salt thereof in step b) is t-butyl. In some embodiments R of the compound of Formula (IV) or a salt thereof in step b) is methyl. In some embodiments the esterifying of the compound of Formula (V) or a salt thereof in step b) is carried out using methanol and hydrochloric acid to obtain compound (IV) or a salt or solvate thereof. In some embodiments the esterifying comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the cyclization in step c) comprises contacting the compound of Formula (IV) or salt thereof with a base.
- the cyclization is performed using potassium tert-butoxide.
- the cyclization is carried out in 2-methyltetrahydrofuran.
- the cyclization comprises treating a compound of Formula (IV) or a salt thereof, for example a compound of (IVa) or a salt thereof, with potassium tert-butoxide in 2-methyltetrahydrofuran.
- the compound of Formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.
- X of the compound of Formula (II) or a salt thereof in step d) is CI, Br, or I. In some embodiments X of the compound of Formula (II) or a salt thereof in step d) is CI.
- the halogenating comprises treating the compound of Formula (III) or a salt thereof with a halogenating agent.
- the halogenating agent is selected from l,3-dichloro-5,5-dimethylhydantoin (DCDMH); N- chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA).
- the halogenating agent is DCDMH and the compound of Formula (II) or a salt thereof is a compound of Formula (Ila) or a salt thereof.
- the aromatizing in step e) is carried out in a suitable solvent and optionally with an additive reagent.
- the aromatizing in step e) is carried out in a suitable solvent which is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone.
- the aromatizing in step e) is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutyl ketone.
- the aromatizing is carried out in acetonitrile in the presence of an additive reagent.
- the additive reagent is a quaternary ammonium salt.
- the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride and tetramethylammonium chloride. In some embodiments the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments the aromatizing is carried out in acetonitrile with tetraetyl ammonium chloride.
- R of step b) is methyl and X of step d) is chloro.
- the compound of Formula (VI) or a salt thereof in step a) is prepared by a process comprising:
- each of Ri and R 2 is independently C 1-4 alkyl, to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VII) or a salt thereof wherein each Ri and R 2 are as defined for the dialkyl malonic ester; iii. hydrolyzing the compound of Formula (VII) or a salt thereof, to form the
- the condensing in step i. comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step i. comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- each of R 1 and R 2 in step ii. is ethyl.
- the dialkyl malonic ester in step ii. is di-tert-butylmalonate or diethyl malonate.
- the adding in step ii. comprises contacting the malonic ester with the compound of Formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.
- the process further comprises purifying the compound of Formula (I) from step e) by crystallization. In some embodiments the process further comprises after step c), step ci) isolating the compound of Formula (III). In some embodiments the process further comprises after step d), step di) isolating the compound of Formula (Ila). In some embodiments the process further comprises purifying the compound of Formula (I) obtained from step e). In some embodiments the purifying comprises crystallization of Formula (I). In some embodiments the compound of Formula (I) is a crystal form described in any embodiment described herein. In some embodiments the compound of Formula (I) is crystal form 1. In some embodiments the compound of Formula (I) is an anhydrous crystal.
- the compound of Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0. ⁇ 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- the compound of Formula (VI) in step a) is prepared by a process comprising: treating methyl isobutyl ketone with tram'-cinnamaldehyde in the presence of methanolic sodium hydroxide to form a compound of Formula (VIII)
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base is selected from imidazole, pyridine, and lutidine (2,6- dimethylpyridine).
- the base is trimethylamine.
- the decarboxylating comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- the compound of Formula (VI) or a salt thereof is prepared by any process described herein.
- the compound of Formula (VI) or a salt thereof is prepared by a process comprising: a) condensing tram'-cinnamaldehyde or a salt thereof with methyl isobutyl
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is trimethylamine. In some embodiments the decarboxylating in step d) comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- the esterifying of the compound of Formula (V) or a salt thereof is carried out using methanol and hydrochloric acid to obtain compound (IVa).
- the esterifying comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the compound of Formula (V) or a salt thereof or a salt thereof is prepared by any method described herein.
- the compound of Formula (V) or a salt thereof is prepared by a process comprising decarboxylating a compound of Formula (VI) or a salt thereof
- the compound of Formula (VI) or a salt thereof is prepared by any process described herein.
- the compound of Formula (VI) or a salt thereof is prepared by a process comprising: i. condensing tram'-cinnamaldehyde or a salt thereof or a salt thereof with methyl isobutyl ketone to form a compound of Formula (VIII) or a salt thereof
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is trimethylamine. In some embodiments the decarboxylating in step d) comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments the esterifying of the compound of Formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (rVa). In some embodiments the esterifying in step e) comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the halogenating comprises treating the compound of Formula (III) or a salt thereof with a halogenating agent.
- the halogenating agent is selected from 1,3- dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide ( CS); and trichloroisocyanuric acid (TCCA).
- the halogenating agent is DCDMH.
- the compound of Formula (III) or a salt thereof is prepared by any process described herein.
- the compound of Formula (III) or a salt thereof is prepared by a process comprising cyclizing a compound of Formula (IVa) or a salt thereof
- the compound of Formula (IVa) or a salt thereof is prepared by any process described herein. In some embodiments the compound of Formula (IVa) or a salt thereof is prepared by a process comprising esterif ing a compoun f Formula (V) or a salt thereof
- the compound of Formula (V) or a salt thereof is prepared by any process described herein. In some embodiments the compound of Formula (V) or a salt thereof is prepared by a process comprising decarboxylating a compound of Formula (VI) or a salt thereof
- the compound of Formula (VI) or a salt thereof is prepared by any process described herein. In some embodiments the compound of Formula (VI) or a salt thereof is prepared by a process comprising: i. condensing tram'-cinnamaldehyde or a salt thereof with methyl isobutyl
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is trimethylamine. In some embodiments the decarboxylating in step d) comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments the esterifying of the compound of Formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (rVa). In some embodiments the esterifying in step e) comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the halogenating in step g) comprises treating the compound of Formula (III) or a salt thereof with a halogenating agent.
- the halogenating agent is selected from l,3-dichloro-5,5-dimethylhydantoin (DCDMH); N- chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA).
- DCDMH l,3-dichloro-5,5-dimethylhydantoin
- NCS N- chlorosuccinimide
- TCCA trichloroisocyanuric acid
- the halogenating agent is DCDMH.
- X is selected from Br, CI and I; and e) aromatizing the compound of Formula (II) or a salt thereof to form the compound of Formula (I) or a salt or solvate thereof.
- Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process further comprises isolating the compound of Formula (III) or a salt thereof. Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process comprises isolating the compound of Formula (II) or a salt thereof. Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process further comprises purifying the compound of Formula I obtained from step e). In some embodiments the purifying comprises crystallization of Formula (I). In some embodiments the compound of Formula (I) is crystal form 1. In some embodiments the compound of Formula (I) is an anhydrous crystal.
- the compound of Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0. ⁇ 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0. ⁇ 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- the decarboxylating of the compound of Formula (VI) or a salt thereof in step a) comprises the presence of a base.
- the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine).
- the base is trimethylamine.
- the decarboxylating comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- R of the compound of Formula (IV) or a salt thereof in step b) is selected from the group consisting of methyl, ethyl, propyl, or butyl. In some embodiments R of the compound of Formula (IV) or a salt thereof in step b) is t-butyl. In some embodiments R of the compound of Formula (IV) or a salt thereof in step b) is methyl. In some embodiments the esterif ing of the compound of Formula (V) or a salt thereof in step b) is carried out using methanol and hydrochloric acid to obtain compound (IV). In some embodiments the esterifying comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the cyclization in step c) comprises contacting the compound of Formula (IV) or salt thereof, with a base.
- the cyclization is performed using potassium tert-butoxide.
- the cyclization is carried out in 2-methyltetrahydrofuran.
- the cyclization comprises treating a compound of Formula (IV) or a salt thereof, for example a compound of (IVa) or a salt thereof, with potassium tert-butoxide in 2-methyltetrahydrofuran.
- the compound of Formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.
- X of the compound of Formula (II) or a salt thereof in step d) is CI, Br, or I. In some embodiments X of the compound of Formula (II) or a salt thereof in step d) is CI.
- the halogenating comprises treating the compound of Formula (III) or a salt thereof with a halogenating agent.
- the halogenating agent is selected from l,3-dichloro-5,5-dimethylhydantoin (DCDMH); N- chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA).
- the halogenating agent is DCDMH and the compound of Formula (II) or a salt thereof is a compound of Formula (Ila) or a salt thereof.
- the aromatizing in step e) is carried out in a suitable solvent and optionally with an additive reagent.
- the aromatizing in step e) is carried out in a suitable solvent which is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone.
- the aromatizing in step e) is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutyl ketone.
- the aromatizing is carried out in acetonitrile in the presence of an additive reagent.
- the additive reagent is a quaternary ammonium salt.
- the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride and tetramethylammonium chloride. In some embodiments the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments the aromatizing is carried out in acetonitrile with tetraetyl ammonium chloride.
- R of step b) is methyl and X of step d) is chloro.
- Some embodiments describe the compound of Formula (I) or a salt thereof wherein the compound of Formula (VI) or a salt thereof is prepared by any process described herein. Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the compound of Formula (VI) or a salt thereof is prepared by a process comprising:
- each of Ri and R 2 is independently C 1-4 alkyl, to the compound of Formula (VIII) or a salt thereof to form a compound of Formula (VII) or a salt thereof wherein each Ri and R 2 are as defined for the dialkyl malonic ester; iii. hydrolyzing the compound of Formula (VII) or a salt thereof to form the
- the condensing in step i. comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step i. comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- each of R 1 and R 2 in step ii. is ethyl.
- the dialkyl malonic ester in step ii. is di-tert-butylmalonate or diethyl malonate.
- the adding in step ii. comprises contacting the malonic ester with the compound of Formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.
- Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process further comprises isolating the compound of Formula (III) or a salt thereof. Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process comprises isolating the compound of Formula (Iia) or a salt thereof. Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process further comprises purifying the compound of Formula (I) obtained from step e). In some embodiments the purifying comprises crystallization of Formula (I). In some embodiments the compound of Formula (I) is crystal form 1. In some embodiments the compound of Formula (I) is an anhydrous crystal.
- the compound of Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0,
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4,
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the decarboxylating of the compound of Formula (VI) or a salt thereof in step a) comprises the presence of a base.
- the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine).
- the base is trimethylamine.
- the decarboxylating comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- the esterif ing of the compound of Formula (V) or a salt thereof in step b) is carried out using methanol and hydrochloric acid to obtain the compound of Formula (IVa).
- the esterifying comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the cyclization in step c) comprises contacting the compound of Formula (IVa) or salt thereof, with a base.
- the cyclization is performed using potassium tert-butoxide.
- the cyclization is carried out in 2-methyltetrahydrofuran.
- the cyclization comprises treating a compound of Formula (IVa) or a salt thereof with potassium tert- butoxide in 2-methyltetrahydrofuran.
- the compound of Formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.
- the halogenating in step d) comprises treating the compound of Formula (III) or a salt thereof with a halogenating agent.
- the halogenating agent is selected from l,3-dichloro-5,5-dimethylhydantoin (DCDMH); N- chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA).
- DCDMH l,3-dichloro-5,5-dimethylhydantoin
- NCS N- chlorosuccinimide
- TCCA trichloroisocyanuric acid
- the halogenating agent is DCDMH.
- the aromatizing in step e) is carried out in a suitable solvent and optionally with an additive reagent.
- the aromatizing in step e) is carried out in a suitable solvent which is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone.
- the aromatizing in step e) is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, acetone and methyl isobutyl ketone.
- the aromatizing is carried out in acetonitrile in the presence of an additive reagent.
- the additive reagent is a quaternary ammonium salt.
- the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride and tetramethylammonium chloride. In some embodiments the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments the aromatizing is carried out in acetonitrile with tetraetyl ammonium chloride.
- Some embodiments describe the compound of Formula (I) or a salt thereof wherein the compound of Formula (VI) or a salt thereof is prepared by any process described herein. Some embodiments describe the compound of Formula (I) or a salt thereof wherein the compound of Formula (VI) or a salt thereof is prepared by a process comprising:
- the condensing in step i. comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step i. comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step ii. comprises contacting the diethyl malonic ester with the compound of Formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.
- Compound of Formula (I) Prepared by Process C
- Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process further comprises isolating the compound of Formula (III). Some embodiments describe the compound of Formula (I) wherein the process comprises isolating the compound of Formula (Ila). Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the process further comprises purifying the compound of Formula (I) obtained from step e). In some embodiments the purifying comprises crystallization of Formula (I). In some embodiments the compound of Formula (I) is crystal form 1. In some embodiments the compound of Formula (I) is an anhydrous crystal. In some embodiments the compound of Formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is in a crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0. ⁇ 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0. ⁇ 2 ⁇ experimental error).
- the compound of Formula (I) is an acetic acid solvate in crystalline solid state characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0. ⁇ 2 ⁇ experimental error).
- Some embodiments describe the compound of Formula (I) or a salt thereof wherein the compound of Formula (VI) or a salt thereof is prepared by any process described herein. Some embodiments describe the compound of Formula (I) or a salt or solvate thereof wherein the compound of Formula (VI) is prepared by a process comprising:
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base is selected from imidazole, pyridine, and lutidine (2,6- dimethylpyridine).
- the base is trimethylamine.
- the decarboxylating comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- the compound of Formula (VI) or a salt thereof is prepared by any process described herein. Some embodiments describe the compound of Formula (V) or a salt thereof wherein the compound of Formula (VI) or a salt thereof is prepared by a process comprising: i. condensing tram'-cinnamaldehyde or a salt thereof with methyl isobutyl
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is trimethylamine. In some embodiments the decarboxylating in step d) comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine.
- the esterifying of the compound of Formula (V) or a salt thereof is carried out using methanol and hydrochloric acid to obtain compound (rVa) or a salt thereof.
- the esterifying comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is trimethylamine. In some embodiments the decarboxylating in step d) comprises heating the compound of Formula or a salt thereof VI in the presence of trimethylamine. In some embodiments the esterifying of the compound of Formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (rVa). In some embodiments the esterifying in step e) comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the halogenating comprises treating the compound of Formula (III) or a salt thereof with a halogenating agent.
- the halogenating agent is selected from 1,3- dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide ( CS); and trichloroisocyanuric acid (TCCA).
- DCDMH 1,3- dichloro-5,5-dimethylhydantoin
- CS N-chlorosuccinimide
- TCCA trichloroisocyanuric acid
- Some embodiments describe the compound of Formula (Ila) or a salt thereof wherein the compound of Formula (IVa) or a salt thereof is prepared by any process described herein. Some embodiments describe the compound of Formula (Ila) or a salt thereof wherein the compound of Formula (IVa) or a salt thereof is prepared by a process comprising esterifying a compound of Formula (V) or a salt thereof
- Some embodiments describe the compound of Formula (Ila) or a salt thereof wherein the compound of Formula (V) or a salt thereof is prepared by any process described herein. Some embodiments describe the compound of Formula (Ila) or a salt thereof wherein the compound of compound of Formula (V) or a salt thereof is prepared by a process comprising decarboxylating a compound of Formula (VI) or a salt thereof
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of lithium, potassium or sodium hydroxide, for example the condensation is performed using potassium or sodium hydroxide in methanol.
- the condensing in step a) comprises treating the methyl isobutyl ketone with the tram'-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.
- the adding in step b) comprises contacting the diethyl malonate with the compound of Formula (Villa) or a salt thereof in the presence of lithium bromide/triethylamine.
- the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is trimethylamine. In some embodiments the decarboxylating in step d) comprises heating the compound of Formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments the esterifying of the compound of Formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (rVa). In some embodiments the esterifying in step e) comprises treating the compound of Formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.
- the halogenating in step g) comprises treating the compound of Formula (III) or a salt thereof with a halogenating agent.
- the halogenating agent is selected from l,3-dichloro-5,5-dimethylhydantoin (DCDMH); N- chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA).
- DCDMH l,3-dichloro-5,5-dimethylhydantoin
- NCS N- chlorosuccinimide
- TCCA trichloroisocyanuric acid
- the halogenating agent is DCDMH.
- a compound of Formula (I) in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 1.
- the compound of Formula (I) in form 1 is characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0. ⁇ 2 ⁇ experimental error).
- the compound of Formula (I) in form 1 is characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees (all values ⁇ 0.1° 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is at least 80% form 1.
- the compound of Formula (I) is at least 85% form 1.
- the compound of Formula (I) is at least 90% form 1.
- the compound of Formula (I) is at least 95% form 1.
- the compound of Formula (I) is at least 99% form 1. In some embodiments the compound of Formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% form 1.
- acetic acid solvate of the compound of Formula (I) is in crystalline solid state form which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
- the acetic acid solvate of the compound of Formula (I) is characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0. ⁇ 2 ⁇ experimental error).
- the acetic acid solvate of the compound of Formula (I) is characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2 ⁇ values, ⁇ 0. ⁇ 2 ⁇ experimental error).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is at least 80% acetic acid solvate of Formula (I).
- the compound of Formula (I) is at least 85% acetic acid solvate of Formula (I).
- the compound of Formula (I) is at least 90% acetic acid solvate of Formula (I).
- the compound of Formula (I) is at least 95% acetic acid solvate of Formula (I). In some embodiments the compound of Formula (I) is at least 99% acetic acid solvate of Formula (I). In some embodiments the compound of Formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%), about 96%), about 97%, about 98%, or about 99% acetic acid solvate of Formula (I).
- the percentage of a particular form of a compound of Formula (I) is expressed in relation to all forms of Formula (I) present in a sample.
- the phrase “the compound of Formula (I) is at least 95% form 1” is meant to convey that at least 95% of all forms of the compound of Formula (I) present is in form 1.
- the phrase “the compound of Formula (I) is at least 80% acetic acid solvate of Formula (I)” means that at least 80% of a sample of the compound of
- Formula (I) is in the form of an acetic acid solvate.
- Embodiments herein describe a pharmaceutical composition comprising a compound of Formula (I) or a salt or solvate thereof prepared according to any embodiment described herein and a pharmaceutically acceptable excipient.
- Some embodiments describe pharmaceutical composition comprising a therapeutically effective amount of compound of Formula (I) of form 1 and a pharmaceutically acceptable excipient.
- the composition of Formula (I) of form 1 is characterised by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees 2 ⁇ ( ⁇ 0. ⁇ 2 ⁇ ).
- the compound of Formula (I) of form 1 is characterised by an X-ray powder diffraction (XRPD) pattern with at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2 and 27.9 degrees degrees 2 ⁇ ( ⁇ 0. ⁇ 2 ⁇ ).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is at least 80% form 1.
- the compound of Formula (I) is at least 85% form 1.
- the compound of Formula (I) is at least 90% form 1.
- the compound of Formula (I) is at least 95% form 1.
- the compound of Formula (I) is at least 99% form 1. In some embodiments the compound of Formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% form 1.
- a pharmaceutical composition comprising a therapeutically effective amount of an acetic acid solvate of the compound of Formula (I) and a pharmaceutically acceptable excipient.
- the acetic acid solvate of the compound of Formula (I) is in a crystalline solid state form which has an X-ray powder diffraction with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2 ⁇ ( ⁇ 0. ⁇ 2 ⁇ ).
- the acetic acid solvate of a compound of Formula (I) is characterised by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2 ⁇ ( ⁇ 0.1° 2 ⁇ ).
- XRPD X-ray powder diffraction
- the compound of Formula (I) is at least 80% acetic acid solvate of Formula (I).
- the compound of Formula (I) is at least 85% acetic acid solvate of Formula (I).
- the compound of Formula (I) is at least 90% acetic acid solvate of Formula (I).
- the compound of Formula (I) is at least 95% acetic acid solvate of Formula (I). In some embodiments the compound of Formula (I) is at least 99% acetic acid solvate of Formula (I). In some embodiments the compound of Formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% acetic acid solvate of Formula (I).
- Some embodiments describe a pharmaceutical composition comprising a compound of Formula (Ila) and a pharmaceutically acceptable excipient. [0144] Some embodiments describe a pharmaceutical composition comprising a compound of Formula (IVa) and a pharmaceutically acceptable excipient.
- compositions comprising a compound of Formula (V) and a pharmaceutically acceptable excipient.
- compositions comprising a compound of Formula (VI) and a pharmaceutically acceptable excipient.
- the compound of Formula (I) is present in a therapeutically effective amount.
- a compound of Formula (I) or a salt or solvate thereof prepared by any process described herein is at least 80% pure by weight. In some embodiments, a compound of Formula (I) or a salt or solvate thereof prepared by any process described herein, is at least 85% pure by weight. In some embodiments, a compound of Formula (I) or a salt or solvate thereof prepared by any process described herein, is at least 90% pure by weight. In some embodiments, a compound of Formula (I) or a salt or solvate thereof prepared by any process described herein, is at least 95% pure by weight.
- a compound of Formula (I) or a salt or solvate thereof prepared by any process described herein is at least 99% pure by weight. In some embodiments, a compound of Formula (I) or a salt or solvate thereof prepared by any process described herein, is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%), or about 99%, pure by weight.
- C 1-4 alkyl means a straight or branched alkyl containing at least one, and at most four, carbon atoms.
- Examples of “C 1-4 alkyl” as used herein include, but are not limited to, methyl, ethyl, ⁇ -propyl, «-butyl, isobutyl, isopropyl and t-butyl.
- references herein to compounds of specified Formulae and “salts thereof cover the compounds as free bases, or as salts thereof, for example as pharmaceutically acceptable salts thereof.
- suitable pharmaceutically acceptable salts see Berge et al, J. Pharm. Set, 66: 1-19, (1977).
- “Solvates” of the compounds of the specified Formulae may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
- Solvates may involve non-aqueous solvents such as ethanol, zso-propyl alcohol, N,N- dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
- non-aqueous solvents such as ethanol, zso-propyl alcohol, N,N- dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
- a "pharmaceutically acceptable excipient” refers to one or more pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered to a patient.
- an X-ray powder diffraction pattern that is "substantially as shown in Figure 1" or “substantially as shown in Figure 2” relates to an X-ray powder diffraction pattern that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the XRPD pattern of Figure 1 or Figure 2. It is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an X-ray powder diffraction pattern may cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern.
- an X-ray powder diffraction pattern that is "substantially as shown in Figure 1" or “substantially as shown in Figure 2" may not necessarily show each of the lines of any one of the diffraction patterns presented herein, and/or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data.
- a person skilled in the art is capable of determining (e.g. by overlaying) if a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their XRPD patterns.
- a "therapeutically effective amount" of a compound, pharmaceutically acceptable salt or solvate thereof or pharmaceutical composition according to any embodiment described herein is an amount sufficient to produce a selected effect on at least one symptom or parameter of a specific disease or disorder.
- the therapeutic effect may be objective (i.e., measurable by some test or marker ) or subjective (i.e., subject gives an indication of or feels an effect or physician observes a change).
- the specific dose of a compound administered according to this disclosure to obtain therapeutic and/or prophylactic effects is determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the coadministration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed and the duration of the treatment;.
- the therapeutically effective amount administered will be determined by the physician in the light of the foregoing relevant circumstances and the exercise of sound medical judgment.
- a therapeutically effective amount of a compound, according to any embodiment described herein, is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.
- the X-ray powder diffraction (XRPD) data were acquired on a PANalytical X'Pert Pro powder diffractometer, model PW3050/60, using an X'Celerator detector.
- the acquisition conditions were: radiation: Cu Ka, generator tension: 45 kV, generator current: 40 mA, step size: 0.017 °2 ⁇ , time per step: 500 seconds, divergence slit type: fixed, divergence slit size: 0.4354 °, measurement temperature: 20-25 °C, goniometer radius: 240 mm.
- the sample was prepared by packing sample in a 0.9 mm capillary, or zero background silicone sample holder. Peak positions were obtained using PANalytical X'Pert Highscore Plus software. The margin of error is approximately ⁇ 0.1° 2 ⁇ for each of the peak assignments.
- Toluene (250 mL) and water (125 mL) were then added directly to the reactor at 0 °C and the stirring biphasic mixture allowed to warm to 20 °C.
- the aqueous layer was removed and the organic layer was washed with water (2 ⁇ 75 mL).
- the washed organic layer was then dried via azeotropic distillation under vacuum to a final solution volume of 75 mL or until analysis via Karl Fischer titration revealed water content less than 0.2%.
- the crude material was utilized in the next transformation without any further processing.
- the heterogeneous reaction mixture was stirred for 2 hours at 20 °C. Water (200 mL) was then charged directly to the stirring reaction mixture. The layers were allowed to separate and the aqueous layer discarded. The resulting product solution was utilized in the next transformation without any further processing.
- the di-tert- butyl malonate addition product (£)-di-tert-butyl 2-(7-methyl-5-oxo-l-phenyloct-l-en-3- yl)malonate (compound of Formula (VII)) could also be isolated via concentration of the toluene solution and crystallization from isopropyl alcohol/water (3 :2) to provide (£)-di-tert- butyl 2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonate (compound of Formula (VII)) as a light yellow solid.
- a concentrated solution of (5E, 7£)-2-methyl-8-phenylocta-5,7-dien-4-one (about 7.6 moles) is diluted with toluene.
- To the solution of (5E, 7£)-2-methyl-8-phenylocta- 5,7-dien-4-one, (compound of Formula (VIII)) in toluene at 20 °C is then added diethyl malonate (1.83kg, 1.73L, 1.5 equiv), triethylamine (1.15kg, 1.58L, 1.5 equiv), and powdered lithium bromide (13 lg, 0.2 equiv).
- the heterogeneous reaction mixture is stirred at 35-40 °C for at least 8 hours.
- the diethyl malonate addition product (£)- diethyl 2-(7-methyl-5-oxo-l-phenyloct-l -en-3-yl)malonate (compound of Formula (Vila)) can also be isolated via concentration of the toluene solution and crystallization to provide (£)-diethyl 2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonate (compound of Formula (Vila)).
- the aqueous layer was cooled to 0-5 °C and the pH was adjusted with cone. HC1 to a pH of 0-1 (required 2.9L or 4.7 equiv), while maintaining the temperature at 10 °C or less during the addition.
- the vessel was charged with TBME (3L, 3 vols) and the biphasic mixture was warmed to 20-25 °C. The mixture was stirred for 15-30 minutes and the layers were separated.
- To the organic layer was added toluene (7L, 7 vols) and water (6L, 6 vols) and the mixture was stirred for 15-30 minutes. The layers were separated and toluene was added to achieve a fill of 16-18 vols (3L, 3vols).
- the mixture was distilled down to about 9-9.5 vols using vacuum distillation, the temperature was adjusted to 40-45 °C and the mixture was seeded with 5g of compound VI (0.2% w/w against theoretical yield). The mixture was stirred at 40-45 °C for 30-60 minutes. Once nucleation was observed the mixture was diluted to 12 volumes with toluene and held at 40-45 °C for at least 1 hour. The slurry was cooled to 10-20 °C at 0.5°C/min and held at 10-20 °C for at least 1 hour. The solid was isolated by filtration and the filter cake was washed with toluene (2x 7 vols).
- Triethylamine (4.4 mL, 31.4 mmol, 0.25 equiv) was charged to a stirred slurry of (7 ⁇ -2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonic acid (compound of Formula (VI)) (40.0 g, 126 mmol, 1 equiv) in toluene (210 mL). The resulting mixture was heated to 1 10 °C and allowed to stir 2 hours.
- the reaction mixture containing the non-isolated intermediate (£)-7-methyl-5-oxo-3-styryloctanoic acid (compound of Formula V) was then allowed to cool to 20 °C and charged with methanol (120 mL) and concentrated aqueous hydrochloric acid (10.5 mL). The resulting solution was stirred for 4 hours at 60 °C.
- the resulting mixture, containing the non-isolated intermediate (£)-methyl 7-methyl-5-oxo-3- styryloctanoate (compound of Formula (IVa)) was allowed to cool to 20 °C and washed with water (200 mL). The washed organic layer was then dried via vacuum distillation to a final solution volume of 120 mL.
- the resulting solution was concentrated to a volume of -610 ml.
- Acetic acid (815 ml) was charged and the solution was concentrated under reduced pressure to a volume of -1.3 L.
- the resultant slurry was heated to 55 °C until homogeneous then cooled slowly to 35 °C over the course of 1 hour during which time product precipitation commenced.
- Methyl cyclohexane (6.5 L) was added to the slurry over the course of 2 hours. Once the addition was complete, the mixture was further cooled to -23 °C over one hour. The solids were filtered and washed twice with 6: 1 methylcyclohexane/AcOH.
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Abstract
Description
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WO2021236709A1 (en) | 2020-05-19 | 2021-11-25 | Teva Pharmaceuticals International Gmbh | Solid state forms of tapinarof |
WO2023067606A1 (en) * | 2021-10-21 | 2023-04-27 | Sol-Gel Technologies Ltd. | Crystalline polymorph of tapinarof |
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US11617724B2 (en) | 2015-05-21 | 2023-04-04 | Dermavant Sciences GmbH | Topical pharmaceutical compositions |
EP3706725A4 (en) | 2017-11-10 | 2021-08-25 | Dermavant Sciences GmbH | Process for preparing tapinarof |
US11497718B2 (en) | 2018-11-13 | 2022-11-15 | Dermavant Sciences GmbH | Use of tapinarof for the treatment of atopic dermatitis |
JP2023523213A (en) * | 2020-04-22 | 2023-06-02 | イッサム リサーチ ディべロップメント カンパニー オブ ザ ヘブライ ユニバーシティー オブ エルサレム,リミテッド | Bioactive phenolate ionic complexes |
CA3198952A1 (en) * | 2020-11-23 | 2022-05-27 | Dermavant Sciences GmbH | Gel, ointment, and foam formulations of tapinarof and methods of use |
CN115703700A (en) * | 2021-08-03 | 2023-02-17 | 北京颖泰嘉和生物科技股份有限公司 | Process for preparing 1, 3-cyclohexanedione |
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